4. Cleaning validation protocols and reports

4.1 Cleaning validation protocols

4.1.1 Cleaning validation should be described in cleaning validation protocols, which should be formally approved, e.g. by the quality control or quality assurance unit.

4.1.2 In preparing the cleaning validation protocol, the following should be considered:

- disassembly of system;

- precleaning;

- cleaning agent, concentration, solution volume, water quality;

- time and temperature;

- flow rate, pressure and rinsing;

- complexity and design of the equipment;

- training of operators; and

- size of the system.

4.1.3 The cleaning validation protocol should include:

• the objectives of the validation process;

• the people responsible for performing and approving the validation study;

• the description of the equipment to be used, including a list of the equipment, make, model, serial number or other unique code;

• the interval between the end of production and the commencement of the cleaning procedure (interval may be part of the validation challenge study itself)

  - the maximum period that equipment may be left dirty before being cleaned as well as the establishment of the time that should elapse after cleaning and before use;

• the levels of microorganisms (bioburden);

• the cleaning procedures (documented in an existing SOP, including definition of any automated process) to be used for each product, each manufacturing system or each piece of equipment;

• all the equipment used for routine monitoring, e.g. conductivity meters, pH meters and total organic carbon analysers;

• the number of cleaning cycles to be performed consecutively;

• the sampling procedures to be used (direct sampling, rinse sampling, inprocess monitoring and sampling locations) and the rationale for their use;

• the data on recovery studies (efficiency of the recovery of the sampling technique should be established);

• the analytical methods (specificity and sensitivity) including the limit of detection and the limit of quantification;

• the acceptance criteria (with rationale for setting the specific limits) including a margin for error and for sampling efficiency;

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• the choice of the cleaning agent should be documented and approved by the quality unit and should be scientifically justified on the basis of, e.g.

  - the solubility of the materials to be removed;

  - the design and construction of the equipment and surface materials to be cleaned;

  - the safety of the cleaning agent;

  - the ease of removal and detection;

  - the product attributes;

  - the minimum temperature and volume of cleaning agent and rinse solution; and

  - the manufacturer's recommendations;

• revalidation requirements.

4.1.4 Cleaning procedures for products and processes which are very similar do not need to be individually validated. A validation study of the “worst case” may be considered acceptable. There should be a justified validation programme for this approach referred to as “bracketing”, addressing critical issues relating to the selected product, equipment or process.

4.1.5 Where “bracketing” of products is done, consideration should be given to type of products and equipment.

4.1.6 Bracketing by product should be done only when the products concerned are similar in nature or property and will be processed using the same equipment. Identical cleaning procedures should then be used for these products.

4.1.7 When a representative product is chosen, this should be the one that is most difficult to clean.

4.1.8 Bracketing by equipment should be done only when it is similar equipment, or the same equipment in different sizes (e.g. 300-l, 500-l and 1000-l tanks). An alternative approach may be to validate the smallest and the largest sizes separately.